Key result
AAV9 gene therapy linked to hepatotoxicity and macrophage activation syndrome in two SMA patients.
Why the study?
Hepatotoxicity is a common and significant adverse effect associated with adeno-associated virus gene therapy, but the underlying mechanisms remain unknown.
Does AAV9 gene therapy with onasemnogene abeparvovec induce hepatotoxicity via macrophage activation in patients with spinal muscular atrophy?
Case Report (n=2)
Does AAV9 gene therapy with onasemnogene abeparvovec induce hepatotoxicity via macrophage activation in patients with spinal muscular atrophy?
AAV9 gene therapy for spinal muscular atrophy can induce hepatotoxicity driven by macrophage activation syndrome, providing a rationale for targeted immunosuppressive therapy.
Hepatotoxicity is a common and significant adverse effect associated with adeno-associated virus (AAV) gene therapy; however, the underlying mechanisms remain unknown. In this study, we demonstrated innate immune activation in two patients with spinal muscular atrophy shortly after receiving AAV9 gene therapy with onasemnogene abeparvovec. Both patients developed marked hyperferritinemia accompanied by hepatotoxicity, thrombocytopenia, hypertriglyceridemia, and hypofibrinogenemia, all of which are the diagnostic criteria for macrophage activation syndrome. To evaluate their immune responses, serial analyses of serum cytokines/chemokines and flow cytometry were performed. Surges in macrophage-associated cytokine levels were observed in proportion to the severity of adverse events within 1 week after AAV vector infusion, suggesting that macrophage activation contributed to the pathogenesis of these adverse effects. Our findings clarify the immunological basis underlying hepatotoxicity in patients after AAV gene therapy. Furthermore, these findings provide a rationale for using various immunosuppressants or chemokine blockers in patients exhibiting severe adverse effects.
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Sakai et al. (2026) conducted a case report in Spinal muscular atrophy (n=2). AAV9 gene therapy (onasemnogene abeparvovec) was evaluated on Innate immune activation and hepatotoxicity. AAV9 gene therapy with onasemnogene abeparvovec induced hepatotoxicity and macrophage activation syndrome in two patients with spinal muscular atrophy.
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